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S1 Supporting Information 1,2-Disubstituted Ferrocenyl Carbohydrate Chloroquine Conjugates as Potential Antimalarial Agents Christoph Herrmann, a,b,c Paloma Salas-Fernandes, c Brian O. Patrick, c Carmen de Cock, d Peter J. Smith, d Michael J. Adam b * and Chris Orvig c * a Advanced Applied Physics Solutions, 4004 Wesbrook Mall, Vancouver, B.C. V6T 2A3, Canada. b TRIUMF, 4004 Wesbrook Mall, Vancouver, B.C. V6T 2A3, Canada. c Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C. V6T 1Z1, Canada. d Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa, and Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa. * To whom correspondence should be addressed. E-mail: [email protected] (M.J.A.), [email protected] (C.O.) Electronic Supplementary Material (ESI) for Dalton Transactions This journal is © The Royal Society of Chemistry 2012

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S1

Supporting Information

1,2-Disubstituted Ferrocenyl Carbohydrate Chloroquine Conjugates as

Potential Antimalarial Agents

Christoph Herrmann,a,b,c Paloma Salas-Fernandes,c Brian O. Patrick,c Carmen de Cock,d Peter J. Smith,d Michael J. Adamb* and Chris Orvigc*

a Advanced Applied Physics Solutions, 4004 Wesbrook Mall, Vancouver, B.C. V6T 2A3, Canada. b TRIUMF, 4004 Wesbrook Mall, Vancouver, B.C. V6T 2A3, Canada. c Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C. V6T 1Z1, Canada. d Department of Medicine, University of Cape Town Medical School, Observatory 7925, South Africa, and Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.

* To whom correspondence should be addressed. E-mail: [email protected] (M.J.A.), [email protected] (C.O.)

Electronic Supplementary Material (ESI) for Dalton TransactionsThis journal is © The Royal Society of Chemistry 2012

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I. Experimental

(2S,4S,Sp)-(+)-1-[6-(1,2;3,5-Diisopropylidene)-α-D-glucofuranosidyl]-2-(4-methoxy-methyl-1,3-dioxan-2-yl)ferrocene (8)

(2S,4S,Sp)-1-Acetoxy-2-(4-methoxymethyl-1,3-dioxan-2-yl) ferrocene (5, 1020 mg, 2.72 mmol, 1 eq.) was dissolved in 100 mL dry DMF and sodium methoxide (162 mg, 3.00 mmol, 1.1 eq.) was added at room temperature. After two hours of stirring at room temperature, a solution of 6-deoxy-6-bromo-(1,2;3,5-diisopropylidene)-α-D-glucofuranose (969 mg, 3.00 mmol, 1.1 eq.) in 30 mL dry DMF was added. The resulting solution was stirred overnight. The following day, the solvent was removed in vacuo and the crude product was purified by column chromatography on silica with a 2 : 1 mixture of hexane/ethyl acetate as eluent (Rf = 0.21). A red waxy solid was yielded after removal of the solvent (915 mg, 1.60 mmol, 59%).

1H NMR (300 MHz, CDCl3, 300 K): δ [ppm] = 6.04 (d, 3JHH = 3.8 Hz, 1H, 1´-H); 5.36 (s, 1H, 6-H); 4.61 (d, 3JHH = 3.8 Hz, 1H, 2´-H); 4.41 (dd, 3JHH = 3.8 Hz, 6.8 Hz, 1H, 4´-H); 4.29 (dd, 3JHH = 5.0 Hz, 2JHH = 11.8 Hz, 1H, 10-HA); 4.26 (m, 1H, 3´-H); 4.20 (s, 5H, Cp-H); 4.13 (m, 1H, 3-H); 4.05 (dd, 3JHH = 3.2 Hz, 2JHH = 10.2 Hz, 1H, 6´-HA); 4.06-3.89 (m, 3H, 8-H, 10-HB; 4-H); 3.94 (dd, 3JHH = 3.2 Hz, 2JHH = 6.8 Hz, 1H, 6´-HB); 3.86 (dd, 3JHH = 3.2 Hz, 6.8 Hz, 1H, 5´-H); 3.79 (m, 1H, 5-H); 3.49 (dd, 3JHH = 5.4 Hz, 2JHH = 10.3 Hz,

1H, 12-HA); 3.38 (dd, 3JHH = 5.2 Hz, 2JHH = 10.3 Hz, 1H, 12-HB); 3.35 (s, 3H, -OCH3); 1.80 (m, 1H, 9-HA); 1.52 (m, 1H, 9-HB); 1.50 (s, 3H, 8´-HA); 1.41 (s, 6H, 10´-HA/B); 1.35 (s, 3H, 8´-HB).

13C{1H} NMR (75 MHz, CDCl3, 300 K): δ [ppm] = 124.6 (C1); 112.3 (C7´); 106.6 (C1´); 101.1 (C9´); 99.1 (C6); 84.2 (C2´); 79.7 (C4´); 76.3 (C8); 75.7 (C2); 75.6 (C3´); 75.2 (C12); 72.1 (C6´); 71.3 (C5´); 69.6 (CpC); 67.3 (C10); 61.4 (C4); 60.9 (C5); 59.4 (-OCH3); 54.6 (C3); 28.5 (C9); 27.4 (C8´A); 26.7 (C8´B); 24.3 (C10´A); 24.2 (C10´B).

Elemental Analysis: (%) calc´d. for C28H38FeO9 (574): C 58.54, H 6.67; found: C 58.28, H 6.67, N 0.18.

ESI+ (Acetonitrile): calc´d for [C28H38FeO9]+ 574.2; found: 574.3; calc´d for [C28H38FeO9 + Na]+

597.2; found: 597.3.

IR (ATR): ν ̄ [cm-1] = 3096 (w), 2985 (m), 2935 (m), 2850 (m), 2121 (w), 1502 (w), 1474 (m), 1449 (m), 1373 (s), 1290 (w), 1240 (m), 1219 (s), 1165 (w), 1143 (w), 1101 (s), 1079 (m), 1000 (s), 958 (w), 916 (w), 859 (m), 816 (m), 732 (w), 526 (w), 493 (s), 469 (m).

Specific Rotation: [α]D20 = -87.5° (0.94, chloroform).

O

Fe

OOO

OO

OOO

34 5

6

8

910

11

1´2´

4´5´

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(Sp)-(+)-1-[6-(1,2;3,5-Diisopropylidene)-α-D-glucofuranosidyl]-2-formylferrocene (9)

The protected ferrocene glucofuranoside conjugate 8 (747 mg, 1.37 mmol, 1 eq.) was dissolved in 100 mL of a 3 : 1 mixture of chloroform / water. Under stirring, p-toluene sulfonic acid monohydrate (519 mg, 2.73 mmol, 2 eq.) was added. The two phase mixture was vigorously stirred and heated to 90 °C under reflux. The colour of the organic phase of the solution changed from yellow to a glowing red. After 3 h, the mixture was cooled to room temperature and the organic layer separated. The aqueous phase was extracted using chloroform (3 x 50 mL each). The combined organic fractions were dried over MgSO4 and, after filtration, the solvent was removed in vacuo to yield a red oil, which was further purified to yield the desired product by column chromatography on silica with hexane / ethyl acetate (2 : 1) as eluant. After evaporation of the solvent in vacuo, a red wax-like product was yielded (520 mg, 1.10 mmol, 80%).

1H NMR (300 MHz, CDCl3, 300 K): δ [ppm] = 10.22 (s, 1H, -CHO); 6.05 (d, 3JHH = 3.8 Hz, 1H, 1´-H); 4.63 (d, 3JHH = 3.8 Hz, 1H, 2´-H); 4.60, 4.35, 4.32 (each m, each 1H, 3,4,5-H); 4.40 (dd, 3JHH = 3.8 Hz, 3JHH = 7.4 Hz, 1H, 4´-H); 4.30 (s, 5H, Cp-H); 4.27 (d, 3JHH = 3.8 Hz, 1H, 3´-H); 4.15 (dd, 3JHH = 2.14, 2JHH = 10.2 Hz, 1H, 6´-HA); 4.00 (dd, 3JHH = 7.1 Hz, 2JHH = 10.2 Hz, 1H, 6´-HB); 3.89 (dt, 3JHH = 2.8 Hz, 3JHH = 7.1 Hz, 1H, 5´-H); 1.52, 1.41, 1.40,

1.35 (each s, each 3H, each –CH3).

13C{1H} NMR (75 MHz, CDCl3, 300 K): δ [ppm] = 192.5 (-CHO); 129.5 (C1); 112.5 (-C(CH3)2); 106.7 (C1´); 101.4 (-C(CH3)2); 84.2 (C2´); 79.5 (C4´); 75.3 (C3´); 71.8 (C6´); 71.2 (C5´); 70.2 (CpC); 69.2 (C2); 66.0 (C4); 61.8 (C5); 57.2 (C3); 27.4, 26.7, 24.14, 24.06 (each –CH3).

ESI+ (Acetonitrile): calc´d for [C23H28FeO7 + Na]+ 495.1; found: 495.2.

Elemental Analysis: (%) calc´d. for C23H28FeO7 (472): C 58.49, H 5.98; found: C 58.35, H 5.84, N 0.03.

IR (ATR): ν̄ [cm-1] = 2987 (w), 2937 (w), 1760 (w), 1674 (vs), 1479 (m), 1454 (m), 1374 (m), 1334 (w), 1287 (w), 1216 (s), 1166 (m), 1107 (m), 1078 (s), 1025 (s), 1001 (m), 891 (w), 850 (m),774 (w).

Specific Rotation: [α]D20 = +402° (0.94, chloroform); +404° (0.26, chloroform).

(Sp)-(-)-2-[2-(7-Chloroquinolin-4-yl-amino)ethylamino]-1-[6-(1,2;3,5-diisopropyl-idene)-α-D-glucofuranosidyl]-ferrocene (16)

The glucofuranose ferrocene 9 (90 mg, 0.19 mmol, 1 eq.) and 10 (105 mg, 0.48 mmol, 2.5 eq.) were dissolved in 15 mL dry THF. After stirring for 15 min, 101 mg of sodium triacetoxyborohydride (0.48 mmol, 2.5 eq.) were added at room temperature. The solution was

Fe

O

OO

O

O

OO

123

4 51´

2´3´

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then stirred for 72 h during which time the red-coloured solution turned yellow and a white precipitate formed. The reaction was quenched by addition of 15 mL of saturated NaHCO3 solution and the mixture extracted using chloroform (3 x 30 mL). The combined organic phases were dried over CaCO3 and after filtration the solvent was removed in vacuo. Purification of the residue was performed through column chromatography on silica, using 2 : 1 :1 (ethyl acetate : hexane : triethylamine). The solvent was removed in vacuo and remaining impurities from the chromatography (silica gel) were removed by taking the residue up in toluene and filtering over a Celite pad. Removal of the solvent yielded an orange wax-like substance (62 mg, 0.09 mmol, 48 %).

1H NMR (300 MHz, CDCl3, 300 K): δ 1H [ppm] = 8.50 (d, 3JHH = 5.3 Hz, 1H, 13-H); 7.93 (d, 4JHH = 1.8 Hz, 1H, 16-H); 7.77 (d, 3JHH = 8.9 Hz, 1H, 19-H); 7.33 (dd, 3JHH = 8.9 Hz, 4JHH = 1.8 Hz, 1H, 18-H); 6.36 (d, 3JHH = 5.3 Hz, 1H, 12-H); 6.05 (br, 1H, NHAr); 6.02 (d, 3JHH = 3.7 Hz, 1H, 1´-H); 4.61 (d, 3JHH = 3.7 Hz, 1H, 2´-H); 4.40 (dd, 3JHH = 3.7 Hz, 3JHH = 6.6 Hz, 1H, 4´-H); 4.26 (d, 3JHH = 3.7 Hz, 1H, 3´-H); 4.15 (s, 5H, Cp-H); 4.06 (dd, 3JHH = 3.7 Hz, 2JHH = 9.5 Hz, 1H, 6´-Ha); 3.99 (m, 1H, 5-H); 3.92 (dd, 4JHH = 6.6 Hz, 2JHH = 9.5 Hz, 1H, 6´-Hb); 3.91 (m, 1H, 3-H); 3.89 (d, 2JHH = 13.5 Hz, 1H, 6-Ha); 3.86 (dd, dm, 3 JHH = 3.7 Hz, 1H, 5´-H); 3.78 (m, 1H, 4-H); 3.50 (d, 2JHH = 13.5 Hz,

1H, 6-Hb); 3.33 (m, 2H, 9-H); 3.01 (m, 2H, 8-H); 2.20 (br, NHAlk); 1.50, 1.32 (each s, each 3H, CH3

1´ and CH32´); 1.37, 1.36 (each s, each 3H, CH3

3´ and CH35´).

13C{1H} NMR (75 MHz, CDCl3, 300 K): δ 13C [ppm] = 152.2 (C13); 150.3 (C15); 149.3 (C11); 135.0 (C17); 128.7 (C16); 125.4 (C18); 125.3 (C1); 121.9 (C19); 117.6 (C20); 112.4 (C(CH3)2

1´2´); 106.7 (C1´); 101.3 (C(CH3)23´5´); 99.3 (C12); 84.0 (C2´); 80.2 (C4´); 75.2 (C3´);

74.9 (C2); 71.3 (C6´); 71.1 (C5´); 69.2 (Cp); 63.9 (C3); 60.5 (C4); 53.4 (C5); 46.5 (C8); 45.6 (C6); 41.9 (C9); 27.4, 26.7 (CH3

1´ and CH32´); 24.2, 24.1 (CH3

3´ and CH35´).

GCOSY (300 / 300 MHz, CDCl3, 300 K) δ 1H / δ 1H [ppm] = 8.50 / 6.36 (13-H / 12-H); 7.77 / 7.33 (19-H / 18-H); 6.05 / 3.33 (NHAr / 9-H); 6.02 / 4.61 (1´-H / 2´-H); 4.40 / 4.26, 3.86 (4´-H / 3´-H, 5´-H); 4.26 / 4.40 (3´-H / 4´-H); 4.06 / 3.92, 3.86 (6´-Ha / 6´-Hb, 5´-H); 3.99 / 3.71 (5-H / 4-H); 3.92 / 4.06, 3.86 (6´-Hb / 6-Ha, 5´-H); 3.91 / 3.78 (3-H / 4-H); 3.89 / 3.50 (6-Ha / 6-Hb); 3.86 / 4.40, 4.06, 3.92 (5´-H / 4´-H, 6´-H, 6´-Ha); 3.78 / 3.99, 3.91 (4-H / 5-H, 3-H); 3.50 / 3.89 (6-Hb / 6-Ha); 3.33 / 6.05, 3.01 (9-H / NHAr, 8-H); 3.01 / 3.33 (8-H / 9-H); 1.50 / 1.32 (CH3

1´2´); 1.37 / 1.36 (CH3

3´5´).

GHSQC (100 / 300 MHz, CDCl3, 300 K) δ 13C / δ 1H [ppm] = 152.2 / 8.50 (C13 / 13-H); 128.7 / 7.93 (C16 / 16-H); 125.4 / 7.33 (C18 / 18-H); 121.9 / 7.77 (C19 / 19-H); 106.7 / 6.02 (C1´ / 6´-H); 99.3 / 6.36 (C12 / 12-H); 84.0 / 4.61 (C2´ / 2´-H); 80.2 / 4.40 (C4´ / 4´-H); 75.2 / 4.26 (C3´ / 3´-H); 71.3 / 4.06, 3.92 (C6´ / 6´-Ha, 6´-Hb); 71.1 / 3.86 (C5´ / 5´-H); 69.2 / 4.15 (Cp / Cp-

Fe

HN

NH

N

Cl

OO

OO

O

O

23

4

68

9

1213

1618

19

1´2´

6´15

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H); 63.9 / 3.91 (C3 / 3-H); 60.5 / 3.78 (C4 / 4-H); 53.4 / 3.99 (C5 / 5-H); 46.5 / 3.01 (C8 / 8-H); 45.6 / 3.89, 3.50 (C6 / 6-Ha, 6-Hb); 41.9 / 3.33 (C9 /9-H); 27.4 / 1.50, 26.7 / 1.32 (each CH3

1´2´ / CH3

1´2´); 24.2 / 1.37, 24.1 / 1.36 (each CH33´5´ / CH3

3´5´).

GHMBC (100 / 300 MHz, CDCl3, 300 K) δ 13C / δ 1H [ppm] = 152.2 / 6.36 (C13 / 12-H); 150.3 / 8.50, 7.77 (C15 / 13-H, 19-H); 149.3 / 8.50, 7.93, 7.77 (C11 / 13-H, 16-H, 19-H); 135.0 / 7.93, 7.77, 7.33 (C17 / 16-H, 19-H, 18-H); 128.7 / 7.33 (C16 / 18-H); 125.4 / 7.93 (C18 / 16-H); 125.3 / 3.89, 3.50 (C1 / 6-Ha, 6-Hb); 121.9 / 6.36 (C19 / 12-H); 117.6 / 8.50, 7.93, 7.77, 7.33, 6.36 (C20 (13-H, 16-H, 19-H, 18-H, 12-H); 112.4 / 6.02, 1.50, 1.32 (C(CH3)2

1´2´ / 1-H´, CH31´2´,

CH31´2´); 106.7 / 4.61, 4.26 (C1´ / 2´-H, 3´-H); 101.3 / 4.26, 1.37, 1.36 (C(CH3)2

3´5´ / 3´-H, CH3

3´5´, CH33´5´); 99.3 / 8.50 (C12 / 13-H); 84.0 / 6.02, 4.26 (C2´ / 1´-H, 3´-H); 80.2 / 6.02, 4.61,

4.26, 4.06, 3.92, 3.86 (C4´ / 1´-H, 2´-H, 3´-H, 6´-Ha, 6´-Hb, 5´-H); 75.2 / 6.02, 4.61, 4.40, 1.37 (C3´ / 1´-H, 2´-H. 4´-H, CH3

3´5´); 74.9 / 3.99, 3.89, 3.78, 3.50 (C2 / 5-H, 6-Ha, 4-H, 6-Hb); 71.3 / 4.40(C6´ / 4´-H); 71.1 / 4.06, 3.92, 1.32 (C5´ / 6´-Ha, 6´-Hb, CH3

3´5´); 69.2 / 4.15 (Cp / Cp-H); 63.9 / 3.99, 3.89, 3.78, 3.50 (C3 / 5-H, 6-Ha, 4-H, 6-Hb); 60.5 / 3.99, 3.89 (C4 / 5-H, 6-Ha); 53.4 / 3.89, 3.78 (C5 / 6-Ha, 4-H); 46.5 / 3.89, 3.50 (C8 / 6-Ha, 6-Hb); 45.6 / 3.01 (C6 / 8-H); 41.9 / 3.01 (C9 / 8-H); 27.4 / 1.32, 26.7 / 1.50 (each CH3

1´2´ / CH31´2´); 24.2 / 1.36, 24.1 / 1.37 (each CH3

3´5´ / CH3

3´5´).

Exact Mass (TOF MS ES+): calc´d for [C34H41N3O635Cl56Fe] 678.2033; found 678.2020.

Elemental Analysis: (%) calc´d. for C34H40ClFeN3O6 (678): C 60.23, H 5.95, N 6.20; found: C 60.46, H 6.42, N 6.19.

IR (ATR): ν̄ [cm-1] = 3307 (br), 2987 (w), 2936 (w), 1611 (w), 1581 (vs), 1533 (w), 1449 (m),

1373 (m), 1330 (w), 1276 (w), 1241 (w), 1221 (m), 1165 (m), 1138 (w), 1104 (w), 1079 (m), 1025 (m), 849 (w), 810 (w), 764 (m), 750 (m), 622 (w).

Specific Rotation: [α]D20 = -87.3° (1.03, chloroform).

(Sp)-(-)-2-[2-(7-Chloroquinolin-4-yl-amino)propylamino]-1-[6-(1,2;3,5-diisopropyl-idene)-α-D-glucofuranosidyl]-ferrocene (17)

In an argon-purged Schlenk tube, 9 (78.4 mg, 0.17 mmol, 1 eq.) and 11 (39.0 mg,0.17 mmol, 1 eq.) were weighed in together and dissolved in 15 mL dry methanol. The solution was stirred under argon for 5 h, during which time the colour changed from red to a dark brown/black. Sodium borohydride (10.3 mg, 0.27 mmol, 1.6 eq.) was added at room temperature. The reaction mixture changed colour to a lighter brown/yellow immediately, under evolution of hydrogen gas. The mixture was then stirred at room temperature for one hour. The reaction was quenched by addition of 1 M NaOH (approximately 5 mL) and addition of 10 mL of brine. The aqueous phase was extracted using diethyl ether (3 x 50 mL). The collected organic phases were dried over MgSO4, and after filtration, the solvent removed in vacuo. The crude product was purified by

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column chromatography on silica, using a 2 : 1 : 1 mixture of ethyl acetate, hexane and triethylamine. Pure product was yielded as an orange, wax-like substance (62 mg, 53 %).

1H NMR (300 MHz CDCl3, 300 K): δ [ppm] = 8.46 (d, 3JHH = 5.4 Hz, 1H, 14-H); 8.09 (br, 1H, NHAr); 7.88 (d, 3JHH = 2.1 Hz, 1H, 17-H); 7.57 (d, 3JHH = 8.9 Hz, 1H, 20-H); 7.18 (dd, 3JHH = 8.9 Hz, 3JHH = 2.1 Hz, 1H, 19-H); 6.26 (d, 3JHH = 5.4 Hz, 1H, 13-H); 6.02 (d, 3JHH = 3.7 Hz, 1H, 1´-H); 4.60 (d, 3JHH = 3.7 Hz, 1H, 2´-H); 4.37 (dd, 3JHH = 7.0 Hz, 3.8 Hz, 1H, 4´-H); 4.24 (d, 3JHH = 3.8 Hz, 1H, 3´-H); 4.17 (s, 5H, Cp-H); 4.06 (dd, 2JHH = 9.8 Hz, 3JHH = 3.8 Hz, 1H, 6´–HA); 4.05 (m, 1H, 3-H); 3.95 (m, 1H, 4-H); 3.94 (d, 2JHH = 12.8 Hz, 1H, 6-HA); 3.88 (m, 1H, 6´-HB); 3.85 (m, 1H, 5-H); 3.84 (dm, 3JHH = 3.8 Hz, 1H, 5´-H); 3.48 (d, 3JHH = 12.8 Hz, 1H, 6-HB); 3.37 (br,

2H, 10-H); 2.93 (m, 2H, 8-H); 1.93 (br, 1H, NHAlk); 1.90 (m, 2H, 9-H); 1.50 (s, 3H, 8´-HA); 1.341 (s, 3H, 8´-HB), 1.337 (s, 3H, 10´-HA), 1.332 (s, 3H, 10´-HB).

13C{1H} NMR (CDCl3, 75 MHz, 300 K): δ [ppm] = 152.2 (C14); 150.9 (C12); 149.3 (C21); 134.6 (C18); 128.4 (C17); 125.6 (C1); 125.0 (C19); 122.9 (C20); 117.8 (C16); 112.4 (C7´); 106.7 (C1´); 101.2 (C9´); 98.2 (C13); 84.1 (C2´); 80.1 (C4´); 75.2 (C3´); 74.9 (C2); 71.4 (C6´); 71.2 (C5´); 69.2 (CpC); 63.9 (C4); 60.5 (C5); 53.5 (C3); 49.3 (C8); 46.6 (C6); 44.4 (C10); 27.4 (C8´A); 27.0 (C9); 26.7 (C8´B); 24.14 (C10´A); 24.09 (C10´B).

GCOSY (300 MHz / 300 MHz ,CDCl3, 300 K): δ (1H) / δ (1H) [ppm] = 8.46 / 6.26 (14-H / 13-H); 8.09 / 3.37 (NHAr / 10-H); 7.88 / 7.18 (17-H / 19-H); 7.57 / 7.18 (20-H / 19-H); 7.18 / 7.88, 7.57 (19-H / 17-H, 20-H); 6.26 / 8.46 (13-H / 14-H); 6.02 / 4.60 (1´-H / 2´-H); 4.60 / 6.02 (2´-H / 1´-H); 4.37 / 4.24, 3.84 (4´-H / 3´-H, 5´-H); 4.24 / 4.37 (3´-H / 4´-H); 4.17 / 4.17 (Cp-H / Cp-H); 4.06 / 3.84 (6´–HA / 5´-H); 4.05 / 3.85 (3-H / 5-H); 3.94 / 3.48 (6-HA / 6-HB); 3.85 / 4.05 (5-H / 3-H); 3.84 / 4.37, 4.06 (5´-H / 4´-H, 6´-HA); 3.48 / 3.94 (6-HB / 6-HA); 3.37 / 1.90 (10-H / 9-H); 2.93 / 1.90 (8-H / 9-H); 1.90 / 3.37, 2.93 (9-H / 10-H, 8-H).

GHMQC (75 MHz / 300 MHz ,CDCl3, 300 K): δ (13C) / δ (1H) [ppm] = 152.2 / 8.46 (C14 / 14-H); 128.4 / 7.88 (C17 / 17-H); 125.0 / 7.18 (C19 / 19-H); 122.9 / 7.57 (C20 /20-H); 106.7 / 6.02 (C1´ / 1´-H); 98.2 / 6.26 (C13 / 13-H); 84.1 / 4.60 (C2´ / 2´-H); 80.1 / 4.37 (C4´ / 4´-H); 75.2 / 4.24 (C3´ / 3´-H); 71.4 / 4.06, 3.88 (C6´ / 6´-HA/B); 71.2 / 3.84 (C5´ / 5´-H); 69.2 / 4.17 (CpC / Cp-H); 63.9 / 3.95 (C4 / 4-H); 60.5 / 3.85 (C5 / 5-H); 53.5 / 4.05 (C3 / 3-H); 49.3 / 2.93 (C8 / 8-H); 46.6 / 3.94, 3.48 (C6 / 6-HA/B); 44.4 / 3.37 (C10 / 10-H); 27.4 / 1.50 (C8´A / 8´-HA); 27.0 / 1.90 (C9 / 9-H); 26.7 / 1.341 (C8´B / 8´-HB); 24.14 / 1.337 (C10´A / 10´-HA); 24.09 / 1.332 (C10´B / 10´-HB).

Fe

NH

OO

OO

O

O

NH

N

Cl

123

45

6

89

1012

13

1416 17

181920

21

5´1´

2´3´

7´8´

9´10´

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GHMBC (75 MHz / 300 MHz, CDCl3, 300 K): δ (13C) / δ (1H) [ppm] = 152.2 / 6.26 (C14 / 13-H); 150.9 / 8.46, 7.57 (C12 / 14-H, 20-H); 149.3 / 8.46, 7.88, 7.57 (C21 / 14-H, 17-H, 20-H); 134.6 / 8.46, 7.88, 7.57, 7.18 (C18 / 14-H, 20-H, 19-H); 128.4 / 7.57, 7.18 (C17 / 20-H, 19-H); 125.6 / 4.05, 3.93, 3.85, 3.48 (C1 / 3-H, 6-HA, 5-H, 6-HB); 125.0 / 7.88 (C19 / 17-H); 122.9 / 6.26 (C20 / 13-H); 117.8 / 8.46, 7.88, 7.57, 7.18, 6.26 (C16 / 14-H, 17-H, 20-H, 19-H, 13-H); 112.4 / 6.02, 1.50, 1.341 (C7´ / 1´-H, 8´-HA/B); 106.7 / 4.60, 4.24 (C1´ / 2´-H, 3´-H); 101.2 / 1.337, 1.332 (C9´ / 10´-HA/B); 98.2 / 8.46 (C13 / 14-H); 84.1 / 6.02, 4.24 (C2´ / 1´-H, 3´-H); 80.1 / 6.02, 4.60, 4.24, 4.06, 3.88 (C4´ / 1´-H, 2´-H, 3´-H, 6´-HA/B); 75.2 / 6.02, 4.60, 4.37, 4.06, 3.84 (C3´ / 1´-H, 2´-H, 4´-H. 6´-HA, 5´-H); 74.9 / 4.05, 3.93, 3.48 (C2 / 3-H, 6-HA/B); 71.2 / 4.37, 4.06, 3.88 (C5´ / 4´-H, 6´-HA/B); 69.2 / 4.17 (CpC / Cp-H); 63.9 / 4.05, 3.93, 3.48 (C4 / 3-H, 6-HA/B); 60.5 / 4.05, 3.95 (C5 / 3-H, 4-H); 53.5 / 3.95, 3.85 (C3 / 4-H, 5-H); 49.3 / 3.93, 3.48, 1.90 (C8 / 6-HA, 6-HB, 9-H); 46.6 / 2.93 (C6 / 8-H); 44.4 / 2.93, 1.90 (C10 / 8-H, 9-H); 27.4 / 1.341 (C8´A / 8´-HB); 27.0 / 3.37, 2.93 (C9 / 10-H, 8-H); 26.7 / 1.50 (C8´B / 8´-HA); 24.14 / 1.334 (C10´A / 10´-HB); 24.09 / 1.332 (C10´B / 10´-HA).

TOF MS ESI+ (MeOH): calc´d for [C35H42ClFeN3O6 + H+] 692.2; found 692.4.

TOF MS ESI- (MeOH): calc´d for [C35H42ClFeN3O6 - H+] 690.2; found 690.4.

Elemental Analysis: (%) calc´d. for C35H42ClFeN3O6 (691): C 60.75, H 6.12, N 6.07; found: C 60.46, H 6.35, N 6.11.

IR (ATR): ν ̄ [cm-1] = 3238 (w), 2987 (m), 2936 (m), 1610 (w), 1582 (s), 1538 (w), 1448 (m), 1373 (m), 1330 (w), 1284 (w), 1239 (w), 1220 (m), 1166 (w), 1139 (w), 1104 (w), 1078 (w), 1025 (m), 853 (w), 803 (w) 766 (w).

Specific Rotation: [α]D20 = -62.2° (0.95, chloroform).

(Sp)-(-)-2-[3-(7-Chloroquinolin-4-yl-amino)-2,2-dimethylpropylamino]-1-[6-(1,2;3,5-diisopropylidene)-α-D-glucofuranosidyl]-ferrocene (18)

The glucofuranose ferrocene 9 (95.5 mg, 0.2 mmol, 1 eq.) was dissolved in 10 mL dry methanol, together 12 (53.2 mg, 0.2 mmol). After stirring for 3 h at room temperature, 13 mg (0.32 mmol) sodium borohydride were added. The solution was then stirred for 1 h during which time the red solution turned yellow. The reaction was quenched by addition of 10 mL 1 M NaOH and the mixture extracted with diethyl ether (3 x 30 mL). The combined organic phases were dried over CaCO3 and after filtration the solvent was removed in vacuo. Purification of the residue was performed through column chromatography on silica, using 2 : 1 : 1 (ethyl acetate : hexane : triethylamine). After collection of the appropriate fractions, the solvent was removed in vacuo. Remaining impurities from the chromatography (silica gel) were removed by taking the residue up in toluene and filtering over a Celite pad. Removal of the solvent yielded an orange wax-like substance (64 mg, 0.09 mmol, 44 %).

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1H NMR (300 MHz, CDCl3, 300 K): δ 1H [ppm] = 8.77 (br, 1H, NHAr); 8.44 (d, 3JHH = 5.4 Hz, 1H; 14-H); 7.87 (d, 4JHH = 2.1 Hz, 1H, 17-H); 7.53 (d, 3JHH = 9.0 Hz, 1H, 20-H); 7.15 (dd, 3JHH = 9.0 Hz, 4JHH = 2.1 Hz, 1H, 19-H); 6.22 (d, 3JHH = 5.4 Hz, 1H, 13-H); 6.02 (d, 3JHH = 3.8 Hz, 1H, 1´-H); 4.60 (d, 3JHH = 3.8 Hz, 1H, 2´-H); 4.36 (dd, 3JHH = 6.8, 3.7 Hz, 1H, 4´-H); 4.24 (d, 3JHH = 3.4 Hz, 1H, 3´-H); 4.16 (s, 5H, Cp-H); 4.05 (m, 1H, 6´-HA); 4.05 (m, 1H, 3-H); 3.95 (m, 1H, 4-H); 3.93 (d,

2JHH = 12.7 Hz, 1H, 6-HA); 3.91 (m, 1H, 6´-HB); 3.87 (m, 1H, 5-H); 3.82 (ddm, 3JHH = 3.6, 6.8 Hz, 1H, 5´-H); 3.44 (d, 2JHH = 12.7 Hz, 1H, 6-HB); 3.12 (m, 2H, 10-H); 2.74 (m, 2H, 8-H); 1.95 (vb, 1H, -NH); 1.49 (s, 3H, 8´-HA); 1.33 (s, 3H, 8´-HB); 1.33 (s, 3H, 10´-HA); 1.32 (s, 3H, 10´-HB); 1.060 (s, 3H, C9CH3

A); 1.055 (s, 3H, C9CH3B).

13C{1H} NMR (75 MHz, CDCl3, 300 K): δ 13C [ppm] = 152.2 (C14); 151.2 (C12); 149.4 (C21); 134.6 (C18); 128.4 (C17); 125.7 (C1); 124.9 (C19); 123.2 (C20); 118.0 (C16); 112.4 (C7´); 106.7 (C1´); 101.2 (C9´); 97.8 (C13); 84.1 (C2´); 80.1 (C4´); 75.2 (C3´); 74.8 (C2); 71.4 (C6´); 71.2 (C5´); 69.2 (CpC); 63.9 (C4); 61.1 (C8); 60.5 (C5); 56.1 (C10); 53.3 (C3); 47.7 (C6); 33.8 (C9); 27.4 (C8´A), 26.7 (C8´B); 25.6 (C9CH3

A); 24.9 (C9CH3B); 24.12 (C10´A); 24.09 (C10´B).

GHSQC (100 / 300 MHz, CDCl3, 300 K) δ 13C / δ 1H [ppm] = 152.2 / 8.44 (C14 / 14-H); 128.4 / 7.87 (C17 / 17-H); 124.9 / 7.15 (C19 / 19-H); 123.2 / 7.53 (C20 / 20-H); 106.7 / 6.02 (C1´ / 1´-H); 97.8 / 6.22 (C13 / 13-H); 84.1 / 4.60 (C2´ / 2´-H); 80.1 / 4.36 (C4´ / 4´-H); 75.2 / 4.24 (C3´ / 3´-H); 71.4 / 4.05, 3.91 (C6´ / 6´-HA/B); 71.2 / 3.82 (C5´ / 5´-H); 69.2 / 4.16 (CpC / Cp-H); 63.9 / 3.95 (C4 / 4-H); 61.1 / 2.74 (C8 / 8-H); 60.5 / 3.87 (C5 / 5-H); 56.1 / 3.12 (C10 / 10-H); 53.3 / 4.05 (C3 / 3-H); 47.7 / 3.93, 3.44 (C6 / 6-HA/B); 27.4 / 1.49 (C8´A / 8´-HA), 26.7 / 1.33 (C8´B / 8´-HB); 25.6 / 1.055 (C9CH3

A / C9CH3A); 24.9 / 1.060 (C9CH3

B / C9CH3B); 24.12 / 1.33

(C10´A / 10´-HA); 24.09 / 1.32 (C10´B / 10´-HB).

GHMBC (100 / 300 MHz, CDCl3, 300 K) δ 13C / δ 1H [ppm] = 152.2 / 6.22 (C14 / 13-H); 151.2 / 8.44, 7.53, 3.12 (C12 / 14-H, 20-H, 10-H); 149.4 / 8.44, 7.87, 7.53 (C21 / 14-H, 17-H, 20-H); 134.6 / 7.87, 7.53, 7.15 (C18 / 17-H, 20-H, 19-H); 128.4 / 7.53, 7.15 (C17 / 20-H, 19-H); 125.7 / 4.05, 3.95, 3.93, 3.87, 3.44 (C1 / 3-H, 4-H, 6-HA, 5-H, 6-HB); 124.9 / 7.87 (C19 / 17-H); 123.2 / 6.22 (C20 / 13-H); 118.0 / 8.44, 7.87, 7.53, 7.15, 6.22 (C16 / 14-H, 17-H, 20-H, 19-H, 13-H); 112.4 / 6.02, 1.49, 1.33 (C7´ / 1´-H, 8´-HA/B); 106.7 / 4.60, 4.24 (C1´ / 2-H´, 3´-H); 101.2 / 4.24, 1.33, 1.32 (C9´ / 3´-H, 10´-HA/B); 97.8 / 8.44 (C13 / 14-H); 84.1 / 6.02, 4.24 (C2´ / 1´-H, 3´-H); 80.1 / 6.02, 4.60, 4.24, 4.05, 3.91, 3.82 (C4´ / 1´-H, 2´-H, 3´-H, 6´-HA, 6´-HB, 5´-H); 75.2 / 6.02, 4.60, 4.36, 1.33 (C3´ / 1´-H, 2´-H, 4´-H, 10´-HA); 74.8 / 4.05, 3.93, 3.87, 3.44 (C2 / 3-H, 6-HA, 5-H, 6-HB); 71.4 / 4.36, 3.82, 1.32 (C6´ / 4´-H, 5´-H, 10´-HB); 71.2 / 4.36, 3.91 (C5´ / 4´-H, 6´-HB); 69.2 / 4.16 (CpC / Cp-H); 63.9 / 4.05, 3.87 (C4 / 3-H, 5-H); 61.1 / 3.44, 3.12, 1.060, 1.055 (C8 / 6-HB, 10-H, C9CH3

A/B); 60.5 / 4.05, 3.95 (C5 / 3-H, 4-H); 56.1 / 2.74, 1.060 (C10 / 8-H, C9CH3

A); 53.3 / 3.95, 3.87 (C3 / 4-H, 5-H); 47.7 / 2.74 (C6 / 8-H); 33.8 / 3.12, 2.74, 1.060, 1.055

Fe

HN

N

Cl

OO

OO

O

O

HN

2´3´

4´5´

6´1

234

5

6

89

10 12

20

14

1617

1819

13

21

10´7´

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(C9 / 10-H, 8-H, C9CH3A/B); 27.4 / 1.33 (C8´A / 8´-HB), 26.7 / 1.49 (C8´B/ 8´-HA); 25.6 / 3.12,

2.74, 1.060 (C9CH3A / 10-H, 8-H, C9CH3

B); 24.9 / 3.12, 2.74, 1.055 (C9CH3B / 10-H, 8-H,

C9CH3A); 24.12 / 1.32 (C10´A / 10´-HB); 24.09 / 1.33 (C10´B / 10´-HA).

Elemental Analysis: (%) calc´d. for C37H46ClFeN3O6 (720): C 61.72, H 6.44, N 5.84; found: C 61.86, H 6.61, N 5.94.

ESI+ (Acetonitrile): calc´d for [C37H46N3O6ClFe + H]+ 720.3; found: 720.7; calc´d for [C37H46N3O6ClFe + Na]+ 742.2; found 742.6.

Exact Mass (TOF MS ES+): calc´d for [C37H47N3O635Cl56Fe]+ 720.2503, found: 720.2487.

IR (ATR): ν ̄ [cm-1] = 3210 (w), 2935 (br), 1609 (w), 1581 (s), 1539 (w), 1447 (m), 1382 (m), 1373 (m), 1332 (w), 1281 (w), 1241 (m), 1220 (m), 1166 (w), 1138 (w), 1079 m), 1028 (w), 902 (w), 852 (m), 805 (w), 766 (w), 669 (w), 649 (w).

Specific Rotation: [α]D20 = -57.2° (0.91, chloroform).

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II X-ray Structure Data Compound 14

Experimental

Data Collection

An orange plate crystal of C23H24N3FeCl having approximate dimensions of 0.03 x 0.35 x 0.45 mm was mounted on a glass fiber. All measurements were made on a Bruker X8 APEX II diffractometer

with graphite monochromated Mo-Kα radiation.

The data were collected at a temperature of -170.0 ± 0.1 °C to a maximum 2θ value of 56.1°. Data

were collected in a series of φ �and ω scans in 0.50° oscillations with 20.0 second exposures. The crystal-to-detector distance was 40.00 mm.

Data Reduction

The material crystallizes as a two-component twin with the two components related by a 180° rotation about the (0 0 1) reciprocal axis. Data were integrated for both twin components, including both overlapped and non-overlapped reflections. In total 37775 reflections were integrated (115458 from component one only, 10844 from component two only, 15383 overlapped). Data were collected and

integrated using the Bruker SAINT1 software packages. The linear absorption coefficient, μ, for Mo-Kα radiation is 9.00 cm-1. Data were corrected for absorption effects using the multi-scan technique (TWINABS2), with minimum and maximum transmission coefficients of 0.605 and 0.973, respectively. The data were corrected for Lorentz and polarization effects.

1 SAINT. Version 7.60A. Bruker AXS Inc., Madison, Wisconsin, USA. (1997-2009). 2 TWINABS. Bruker Nonius scaling and absorption for twinned crystals – V2008/2, Bruker AXS Inc., Madison, Wisconsin, USA

(2007).

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Structure Solution and Refinement

The structure was solved by direct methods3 using non-overlapped data from the major twin component. Subsequent refinements were carried out using an HKLF 5 format data set containing complete data from component 1 and any overlapped reflections from component 2. All non-hydrogen atoms were refined anisotropically. All N-H hydrogen atoms were located in difference maps and refined isotropically. All other hydrogen atoms were included in calculated positions but not refined. The batch scale refinement showed a roughly 55:45 ratio between the major and minor twin components. The final cycle of full-matrix least-squares refinement4 on F2 was based on 4847 reflections and 262 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of:

R1 = Σ ||Fo| - |Fc|| / Σ |Fo| = 0.055

wR2 = [ Σ ( w (Fo2 – Fc2)2)/ Σ w(Fo2)2]1/2 = 0.089

The standard deviation of an observation of unit weight5 was 1.14. The weighting scheme was based on counting statistics. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.46 and –0.47 e-/Ǻ3, respectively.

Neutral atom scattering factors were taken from Cromer and Waber. 6 Anomalous dispersion

effects were included in Fcalc7; the values for Δf' and Δf" were those of Creagh and McAuley.8 The values for the mass attenuation coefficients are those of Creagh and Hubbell.9 All refinements were performed using the SHELXTL10 crystallographic software package of Bruker-AXS.

EXPERIMENTAL DETAILS

A. Crystal Data Empirical Formula C23H24N3FeCl Formula Weight 433.75 Crystal Colour, Habit orange, plate Crystal Dimensions 0.03 X 0.35 X 0.45 mm Crystal System monoclinic Lattice Type primitive Lattice Parameters a = 16.418(2) Å b = 10.201(1) Å

3 SIR97 - Altomare A., Burla M.C., Camalli M., Cascarano G.L., Giacovazzo C. , Guagliardi A., Moliterni A.G.G., Polidori G.,Spagna R. (1999) J. Appl. Cryst. 32, 115-119.

4 Least Squares function minimized: Σw(Fo2-Fc

2)2 5 Standard deviation of an observation of unit weight: [Σw(Fo

2 – Fc2)2/(No-Nv)]1/2

where: No = number of observations Nv = number of variables 6 Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham,

England, Table 2.2 A (1974). 7 Ibers, J. A. & Hamilton, W. C.; Acta Crystallogr., 17, 781 (1964). 8 Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic

Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992). 9 Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic

Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992). 10 SHELXTL Version 5.1. Bruker AXS Inc., Madision, Wisconsin, USA. (1997).

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c = 12.6323(1) Å

α = 90.0°

β = 108.828(4)°

γ = 90.0° V = 2002.4(3) Å3 Space Group P 21/c (#14) Z value 4 Dcalc 1.439 g/cm3 F000 904.00

μ(MoKα) 9.00 cm-1

B. Intensity Measurements

Diffractometer Bruker X8 APEX II

Radiation MoKα (λ = 0.71073 Å) graphite monochromated Data Images 1547 exposures @ 20.0 seconds Detector Position 40.00 mm

2θmax 56.1° No. of Reflections Measured Total: 37775 Unique: 4847, both components (Rint = 0.057) Corrections Absorption (Tmin = 0.605, Tmax= 0.973) Lorentz-polarization

C. Structure Solution and Refinement

Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares on F2

Function Minimized Σ w (Fo2 – Fc2)2

Least Squares Weights w=1/(σ2(Fo2)+(0.0170P)2+ 2.3835P) Anomalous Dispersion All non-hydrogen atoms

No. Observations (I>0.00σ(I)) 4847 No. Variables 262 Reflection/Parameter Ratio 18.50 Residuals (refined on F2, all data): R1; wR2 0.055; 0.089 Goodness of Fit Indicator 1.14

No. Observations (I>2.00σ(I)) 4177 Residuals (refined on F): R1; wR2 0.039; 0.080 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.46 e-/Å3 Minimum peak in Final Diff. Map -0.47 e-/Å3

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Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for 14. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ___________________________________________ x y z U(eq) ___________________________________________ C(1) 12924(2) 1012(3) 14885(2) 17(1) C(2) 13572(2) 1978(3) 15343(2) 22(1) C(3) 13558(2) 2322(3) 16421(2) 22(1) C(4) 12905(2) 1580(3) 16650(2) 22(1) C(5) 12512(2) 773(3) 15702(2) 19(1) C(6) 12694(2) 429(3) 13745(2) 18(1) C(8) 11763(2) 690(3) 11821(2) 16(1) C(9) 11009(2) 1463(3) 11064(2) 16(1) C(10) 10849(2) 1126(3) 9842(2) 17(1) C(12) 9819(2) 1655(3) 8002(2) 14(1) C(13) 10239(2) 837(3) 7467(2) 17(1) C(14) 9957(2) 756(3) 6305(2) 17(1) C(16) 8855(2) 2184(2) 6119(2) 14(1) C(17) 8138(2) 2881(3) 5417(2) 15(1) C(18) 7658(2) 3653(3) 5867(2) 16(1) C(19) 7845(2) 3781(3) 7028(2) 16(1) C(20) 8548(2) 3138(3) 7719(2) 14(1) C(21) 9074(2) 2340(2) 7297(2) 12(1) C(22) 14362(2) -1303(3) 16039(3) 24(1) C(23) 14981(2) -294(3) 16417(3) 26(1) C(24) 14988(2) 106(3) 17493(3) 26(1) C(25) 14371(2) -670(3) 17785(3) 24(1) C(26) 13986(2) -1533(3) 16888(3) 25(1) N(2) 10089(2) 1799(2) 9126(2) 16(1) N(7) 11965(2) 1133(2) 12976(2) 19(1) N(15) 9301(1) 1412(2) 5615(2) 15(1) Cl(1) 6799(1) 4535(1) 4988(1) 23(1) Fe(1) 13800(1) 374(1) 16353(1) 15(1) Bond lengths [A] and angles [deg] for 14. __________________________ C(1)-C(5) 1.426(4) C(1)-C(2) 1.428(4) C(1)-C(6) 1.490(4) C(1)-Fe(1) 2.052(3) C(2)-C(3) 1.414(4) C(2)-Fe(1) 2.034(3) C(2)-H(2) 0.9500 C(3)-C(4) 1.418(4) C(3)-Fe(1) 2.033(3) C(3)-H(3) 0.9500 C(4)-C(5) 1.424(4) C(4)-Fe(1) 2.042(3) C(4)-H(4) 0.9500 C(5)-Fe(1) 2.047(3) C(5)-H(5) 0.9500 C(6)-N(7) 1.463(3) C(6)-H(6A) 0.9900 C(6)-H(6B) 0.9900 C(8)-N(7) 1.459(3) C(8)-C(9) 1.518(3) C(8)-H(8A) 0.9900 C(8)-H(8B) 0.9900 C(9)-C(10) 1.519(4) C(9)-H(9A) 0.9900 C(9)-H(9B) 0.9900 C(10)-N(2) 1.454(3) C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900 C(12)-N(2) 1.353(3) C(12)-C(13) 1.389(4) C(12)-C(21) 1.440(3) C(13)-C(14) 1.391(4) C(13)-H(13) 0.9500 C(14)-N(15) 1.328(3) C(14)-H(14) 0.9500 C(16)-N(15) 1.365(3) C(16)-C(17) 1.415(3) C(16)-C(21) 1.423(3) C(17)-C(18) 1.361(4) C(17)-H(17) 0.9500

C(18)-C(19) 1.405(4) C(18)-Cl(1) 1.738(3) C(19)-C(20) 1.369(4) C(19)-H(19) 0.9500 C(20)-C(21) 1.410(4) C(20)-H(20) 0.9500 C(22)-C(23) 1.417(4) C(22)-C(26) 1.418(4) C(22)-Fe(1) 2.042(3) C(22)-H(22) 0.9500 C(23)-C(24) 1.416(5) C(23)-Fe(1) 2.033(3) C(23)-H(23) 0.9500 C(24)-C(25) 1.424(4) C(24)-Fe(1) 2.034(3) C(24)-H(24) 0.9500 C(25)-C(26) 1.413(4) C(25)-Fe(1) 2.047(3) C(25)-H(25) 0.9500 C(26)-Fe(1) 2.049(3) C(26)-H(26) 0.9500 N(2)-H(2N) 0.77(3) N(7)-H(7N) 0.79(3) C(5)-C(1)-C(2) 106.8(3) C(5)-C(1)-C(6) 126.9(3) C(2)-C(1)-C(6) 126.2(3) C(5)-C(1)-Fe(1) 69.45(15) C(2)-C(1)-Fe(1) 68.88(15) C(6)-C(1)-Fe(1) 129.2(2) C(3)-C(2)-C(1) 108.7(3) C(3)-C(2)-Fe(1) 69.63(16) C(1)-C(2)-Fe(1) 70.21(15) C(3)-C(2)-H(2) 125.6 C(1)-C(2)-H(2) 125.6 Fe(1)-C(2)-H(2) 126.1 C(2)-C(3)-C(4) 108.2(2) C(2)-C(3)-Fe(1) 69.70(16) C(4)-C(3)-Fe(1) 69.98(16) C(2)-C(3)-H(3) 125.9 C(4)-C(3)-H(3) 125.9 Fe(1)-C(3)-H(3) 126.0 C(3)-C(4)-C(5) 107.7(3) C(3)-C(4)-Fe(1) 69.31(16) C(5)-C(4)-Fe(1) 69.79(16) C(3)-C(4)-H(4) 126.2 C(5)-C(4)-H(4) 126.2 Fe(1)-C(4)-H(4) 126.3 C(4)-C(5)-C(1) 108.6(2) C(4)-C(5)-Fe(1) 69.44(15) C(1)-C(5)-Fe(1) 69.84(15) C(4)-C(5)-H(5) 125.7 C(1)-C(5)-H(5) 125.7 Fe(1)-C(5)-H(5) 126.6 N(7)-C(6)-C(1) 110.1(2) N(7)-C(6)-H(6A) 109.6 C(1)-C(6)-H(6A) 109.6 N(7)-C(6)-H(6B) 109.6 C(1)-C(6)-H(6B) 109.6 H(6A)-C(6)-H(6B) 108.1 N(7)-C(8)-C(9) 110.2(2) N(7)-C(8)-H(8A) 109.6 C(9)-C(8)-H(8A) 109.6 N(7)-C(8)-H(8B) 109.6 C(9)-C(8)-H(8B) 109.6 H(8A)-C(8)-H(8B) 108.1 C(8)-C(9)-C(10) 111.2(2) C(8)-C(9)-H(9A) 109.4 C(10)-C(9)-H(9A) 109.4 C(8)-C(9)-H(9B) 109.4 C(10)-C(9)-H(9B) 109.4 H(9A)-C(9)-H(9B) 108.0 N(2)-C(10)-C(9) 111.0(2) N(2)-C(10)-H(10A) 109.4 C(9)-C(10)-H(10A) 109.4 N(2)-C(10)-H(10B) 109.4 C(9)-C(10)-H(10B) 109.4 H(10A)-C(10)-H(10B) 108.0 N(2)-C(12)-C(13) 122.0(2)

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N(2)-C(12)-C(21) 121.5(2) C(13)-C(12)-C(21) 116.6(2) C(12)-C(13)-C(14) 120.1(2) C(12)-C(13)-H(13) 120.0 C(14)-C(13)-H(13) 120.0 N(15)-C(14)-C(13) 125.8(3) N(15)-C(14)-H(14) 117.1 C(13)-C(14)-H(14) 117.1 N(15)-C(16)-C(17) 117.4(2) N(15)-C(16)-C(21) 124.0(2) C(17)-C(16)-C(21) 118.5(2) C(18)-C(17)-C(16) 120.3(2) C(18)-C(17)-H(17) 119.8 C(16)-C(17)-H(17) 119.8 C(17)-C(18)-C(19) 122.0(2) C(17)-C(18)-Cl(1) 119.5(2) C(19)-C(18)-Cl(1) 118.5(2) C(20)-C(19)-C(18) 118.5(3) C(20)-C(19)-H(19) 120.8 C(18)-C(19)-H(19) 120.8 C(19)-C(20)-C(21) 121.9(2) C(19)-C(20)-H(20) 119.0 C(21)-C(20)-H(20) 119.0 C(20)-C(21)-C(16) 118.7(2) C(20)-C(21)-C(12) 123.3(2) C(16)-C(21)-C(12) 118.0(2) C(23)-C(22)-C(26) 107.8(3) C(23)-C(22)-Fe(1) 69.28(17) C(26)-C(22)-Fe(1) 70.00(17) C(23)-C(22)-H(22) 126.1 C(26)-C(22)-H(22) 126.1 Fe(1)-C(22)-H(22) 126.2 C(24)-C(23)-C(22) 108.4(3) C(24)-C(23)-Fe(1) 69.69(18) C(22)-C(23)-Fe(1) 70.03(17) C(24)-C(23)-H(23) 125.8 C(22)-C(23)-H(23) 125.8 Fe(1)-C(23)-H(23) 126.0 C(23)-C(24)-C(25) 107.6(3) C(23)-C(24)-Fe(1) 69.55(16) C(25)-C(24)-Fe(1) 70.06(16) C(23)-C(24)-H(24) 126.2 C(25)-C(24)-H(24) 126.2 Fe(1)-C(24)-H(24) 125.8 C(26)-C(25)-C(24) 108.0(3) C(26)-C(25)-Fe(1) 69.91(17) C(24)-C(25)-Fe(1) 69.10(16) C(26)-C(25)-H(25) 126.0 C(24)-C(25)-H(25) 126.0 Fe(1)-C(25)-H(25) 126.6 C(25)-C(26)-C(22) 108.2(3) C(25)-C(26)-Fe(1) 69.74(17) C(22)-C(26)-Fe(1) 69.46(17) C(25)-C(26)-H(26) 125.9 C(22)-C(26)-H(26) 125.9 Fe(1)-C(26)-H(26) 126.5 C(12)-N(2)-C(10) 121.8(2) C(12)-N(2)-H(2N) 120(2) C(10)-N(2)-H(2N) 118(2) C(8)-N(7)-C(6) 112.7(2) C(8)-N(7)-H(7N) 107(2) C(6)-N(7)-H(7N) 109(2) C(14)-N(15)-C(16) 115.4(2) C(23)-Fe(1)-C(3) 121.52(13) C(23)-Fe(1)-C(2) 105.97(12) C(3)-Fe(1)-C(2) 40.67(12) C(23)-Fe(1)-C(24) 40.75(13) C(3)-Fe(1)-C(24) 104.90(12) C(2)-Fe(1)-C(24) 119.53(12) C(23)-Fe(1)-C(4) 158.27(13) C(3)-Fe(1)-C(4) 40.72(12) C(2)-Fe(1)-C(4) 68.48(12) C(24)-Fe(1)-C(4) 122.23(12) C(23)-Fe(1)-C(22) 40.69(13) C(3)-Fe(1)-C(22) 158.94(13) C(2)-Fe(1)-C(22) 123.73(13) C(24)-Fe(1)-C(22) 68.60(13) C(4)-Fe(1)-C(22) 159.57(13) C(23)-Fe(1)-C(5) 158.63(13)

C(3)-Fe(1)-C(5) 68.44(11) C(2)-Fe(1)-C(5) 68.33(11) C(24)-Fe(1)-C(5) 160.21(13) C(4)-Fe(1)-C(5) 40.77(11) C(22)-Fe(1)-C(5) 124.13(12) C(23)-Fe(1)-C(25) 68.35(13) C(3)-Fe(1)-C(25) 120.75(12) C(2)-Fe(1)-C(25) 155.80(12) C(24)-Fe(1)-C(25) 40.84(12) C(4)-Fe(1)-C(25) 107.62(12) C(22)-Fe(1)-C(25) 68.21(12) C(5)-Fe(1)-C(25) 125.28(12) C(23)-Fe(1)-C(26) 68.24(12) C(3)-Fe(1)-C(26) 157.53(13) C(2)-Fe(1)-C(26) 161.41(12) C(24)-Fe(1)-C(26) 68.41(12) C(4)-Fe(1)-C(26) 123.43(12) C(22)-Fe(1)-C(26) 40.54(12) C(5)-Fe(1)-C(26) 110.25(12) C(25)-Fe(1)-C(26) 40.35(12) C(23)-Fe(1)-C(1) 121.58(12) C(3)-Fe(1)-C(1) 68.83(11) C(2)-Fe(1)-C(1) 40.91(11) C(24)-Fe(1)-C(1) 156.16(12) C(4)-Fe(1)-C(1) 68.84(11) C(22)-Fe(1)-C(1) 108.58(12) C(5)-Fe(1)-C(1) 40.71(11) C(25)-Fe(1)-C(1) 162.03(12) C(26)-Fe(1)-C(1) 125.82(12) _______________________________ Symmetry transformations used to generate equivalent atoms:

Hydrogen Bonds in 14. Donor --- H....Acceptor [ ARU ] D - H H...A D...A D - H...A -------------------------------------------------------------------------------- N(2) --H(2N) ..N(15) [ 4555.01] 0.77(3) 2.42(3) 3.180(3) 168(3)

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III X-ray Structure Data: Compound 15

Experimental

Data Collection

An irregular red crystal of C25H28N3FeCl x C7H8 having approximate dimensions of 0.10 x 0.25 x 0.35 mm was mounted on a glass fiber. All measurements were made on a Bruker APEX II diffractometer with graphite monochromated Mo-Kα radiation.

The data were collected at a temperature of -170.0 ± 0.1 °C to a maximum 2θ value of 56.1°. Data were

collected in a series of φ and ω scans in 0.50° oscillations with 10.0-second exposures. The crystal-to-detector distance was 40.00 mm.

Data Reduction

Of the 75057 reflections that were collected, 6611 were unique (Rint = 0.040); equivalent

reflections were merged. Data were collected and integrated using the Bruker SAINT1 software package.

The linear absorption coefficient, μ, for Mo-Kα radiation is 6.77 cm-1. Data were corrected for absorption

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effects using the multi-scan technique (SADABS 11 ), with minimum and maximum transmission coefficients of 0.823 and 0.935, respectively. The data were corrected for Lorentz and polarization effects.

Structure Solution and Refinement

The structure was solved by direct methods.3 The material crystallizes with toluene in the lattice. All non-hydrogen atoms were refined anisotropically. All N-H hydrogen atoms were located in difference maps and refined isotropically. All other hydrogen atoms were placed in calculated positions. The final

cycle of full-matrix least-squares refinement4 on F2 was based on 6611 reflections and 345 variable parameters and converged (largest parameter shift was 0.00 times its esd) with unweighted and weighted agreement factors of:

R1 = Σ ||Fo| - |Fc|| / Σ |Fo| = 0.046

wR2 = [ Σ ( w (Fo2 – Fc2)2 )/ Σ w(Fo2)2]1/2 = 0.096

The standard deviation of an observation of unit weight5 was 1.05. The weighting scheme was based on counting statistics. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.45 and –0.52 e-/Å3, respectively.

Neutral atom scattering factors were taken from Cromer and Waber.6 Anomalous dispersion

effects were included in Fcalc;7 the values for Δf' and Δf" were those of Creagh and McAuley.8 The values for the mass attenuation coefficients are those of Creagh and Hubbell.9 All refinements were performed using the SHELXL-9710 via the WinGX12 interface.

EXPERIMENTAL DETAILS

A. Crystal Data

Empirical Formula C32H36N3FeCl Formula Weight 553.94 Crystal Colour, Habit red, irregular Crystal Dimensions 0.10 X 0.25 X 0.35 mm Crystal System orthorhombic Lattice Type primitive Lattice Parameters a = 13.1852(5) Å b = 18.4105(7) Å c = 22.4888(9) Å

α = 90°

β = 90°

γ = 90° V = 5459.1(4) Å3

11 SADABS. Bruker Nonius area detector scaling and absorption correction - V2008/1, Bruker AXS Inc., Madison, Wisconsin, USA (2008).

12 WinGX – V1.70 – Farrugia, L.J.; J. Appl. Cryst., 32, 837 (1999).

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Space Group P bca (#61) Z value 8 Dcalc 1.348 g/cm3 F000 2336.00

μ(MoKα) 6.77 cm-1 B. Intensity Measurements Diffractometer Bruker X8 APEX II

Radiation MoKα (λ = 0.71073 Å) graphite monochromated Data Images 1413 exposures @ 10.0 seconds Detector Position 40.00 mm

2θmax 56.1°

No. of Reflections Measured Total: 75057 Unique: 6611(Rint = 0.040) Corrections Absorption (Tmin = 0.823, Tmax= 0.935) Lorentz-polarization

C. Structure Solution and Refinement

Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares on F2

Function Minimized Σ w (Fo2 – Fc2)2

Least Squares Weights w=1/(σ2(Fo2)+(0.0473P)2+ 3.4742P) Anomalous Dispersion All non-hydrogen atoms

No. Observations (I>0.00σ(I)) 6611 No. Variables 345 Reflection/Parameter Ratio 19.16 Residuals (refined on F2, all data): R1; wR2 0.046; 0.096 Goodness of Fit Indicator 1.05

No. Observations (I>2.00σ(I)) 5423 Residuals (refined on F): R1; wR2 0.033; 0.087 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.45 e-/Å3 Minimum peak in Final Diff. Map -0.52 e-/Å3

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Atomic coordinates ( x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for 15. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ___________________________________________ x y z U(eq) ___________________________________________ C(1) 7737(1) 711(1) 4265(1) 19(1) C(2) 7302(1) 1163(1) 4715(1) 23(1) C(3) 6274(1) 953(1) 4797(1) 24(1) C(4) 6061(1) 378(1) 4394(1) 23(1) C(5) 6960(1) 227(1) 4067(1) 20(1) C(6) 8799(1) 750(1) 4029(1) 20(1) C(8) 9827(1) 1000(1) 3153(1) 20(1) C(9) 9874(1) 1296(1) 2514(1) 21(1) C(10) 9650(1) 2117(1) 2494(1) 22(1) C(12) 8239(1) 2940(1) 2781(1) 20(1) C(13) 8546(1) 3515(1) 2416(1) 24(1) C(14) 7990(1) 4162(1) 2419(1) 27(1) C(16) 6864(1) 3750(1) 3105(1) 21(1) C(17) 6000(1) 3877(1) 3461(1) 24(1) C(18) 5691(1) 3369(1) 3865(1) 23(1) C(19) 6207(1) 2707(1) 3939(1) 22(1) C(20) 7030(1) 2567(1) 3587(1) 19(1) C(21) 7374(1) 3072(1) 3157(1) 19(1) C(22) 9134(2) 891(1) 2108(1) 28(1) C(23) 10956(1) 1183(1) 2286(1) 31(1) C(24) 7952(2) -33(1) 5751(1) 35(1) C(25) 6922(2) -249(1) 5803(1) 29(1) C(26) 6749(1) -819(1) 5390(1) 26(1) C(27) 7670(1) -951(1) 5080(1) 30(1) C(28) 8412(1) -464(1) 5304(1) 35(1) C(29) 8713(1) -2724(1) 6117(1) 28(1) C(30) 8963(2) -3359(1) 6424(1) 33(1) C(31) 9884(2) -3699(1) 6339(1) 33(1) C(32) 10581(2) -3417(1) 5943(1) 32(1) C(33) 10349(1) -2788(1) 5632(1) 28(1) C(34) 9419(1) -2447(1) 5716(1) 25(1) C(35) 7717(2) -2349(1) 6220(1) 42(1) N(7) 8794(1) 956(1) 3396(1) 19(1) N(11) 8701(1) 2289(1) 2792(1) 22(1) N(15) 7171(1) 4300(1) 2736(1) 26(1) Cl(1) 4637(1) 3544(1) 4310(1) 33(1) Fe(1) 7212(1) 95(1) 4956(1) 18(1) ___________________________________________ Bond lengths [A] and angles [deg] for 15. ___________________________________________ C(1)-C(5) 1.428(2) C(1)-C(2) 1.431(2) C(1)-C(6) 1.499(2) C(1)-Fe(1) 2.0451(15) C(2)-C(3) 1.422(2) C(2)-Fe(1) 2.0436(16) C(2)-H(2) 0.9500 C(3)-C(4) 1.422(2) C(3)-Fe(1) 2.0388(17) C(3)-H(3) 0.9500 C(4)-C(5) 1.422(2) C(4)-Fe(1) 2.0418(17) C(4)-H(4) 0.9500 C(5)-Fe(1) 2.0401(16) C(5)-H(5) 0.9500 C(6)-N(7) 1.474(2) C(6)-H(6A) 0.9900 C(6)-H(6B) 0.9900 C(8)-N(7) 1.470(2) C(8)-C(9) 1.539(2)

C(8)-H(8A) 0.9900 C(8)-H(8B) 0.9900 C(9)-C(23) 1.529(2) C(9)-C(22) 1.530(2) C(9)-C(10) 1.541(2) C(10)-N(11) 1.455(2) C(10)-H(10A) 0.9900 C(10)-H(10B) 0.9900 C(12)-N(11) 1.345(2) C(12)-C(13) 1.399(2) C(12)-C(21) 1.440(2) C(13)-C(14) 1.399(2) C(13)-H(13) 0.9500 C(14)-N(15) 1.319(2) C(14)-H(14) 0.9500 C(16)-N(15) 1.371(2) C(16)-C(17) 1.412(2) C(16)-C(21) 1.423(2) C(17)-C(18) 1.365(2) C(17)-H(17) 0.9500 C(18)-C(19) 1.406(2) C(18)-Cl(1) 1.7436(18) C(19)-C(20) 1.369(2) C(19)-H(19) 0.9500 C(20)-C(21) 1.415(2) C(20)-H(20) 0.9500 C(22)-H(22A) 0.9800 C(22)-H(22B) 0.9800 C(22)-H(22C) 0.9800 C(23)-H(23A) 0.9800 C(23)-H(23B) 0.9800 C(23)-H(23C) 0.9800 C(24)-C(28) 1.417(3) C(24)-C(25) 1.420(3) C(24)-Fe(1) 2.0498(19) C(24)-H(24) 0.9500 C(25)-C(26) 1.420(3) C(25)-Fe(1) 2.0443(17) C(25)-H(25) 0.9500 C(26)-C(27) 1.422(2) C(26)-Fe(1) 2.0387(16) C(26)-H(26) 0.9500 C(27)-C(28) 1.419(3) C(27)-Fe(1) 2.0368(18) C(27)-H(27) 0.9500 C(28)-Fe(1) 2.0420(18) C(28)-H(28) 0.9500 C(29)-C(34) 1.393(2) C(29)-C(30) 1.397(3) C(29)-C(35) 1.502(3) C(30)-C(31) 1.379(3) C(30)-H(30) 0.9500 C(31)-C(32) 1.382(3) C(31)-H(31) 0.9500 C(32)-C(33) 1.387(3) C(32)-H(32) 0.9500 C(33)-C(34) 1.391(3) C(33)-H(33) 0.9500 C(34)-H(34) 0.9500 C(35)-H(35A) 0.9800 C(35)-H(35B) 0.9800 C(35)-H(35C) 0.9800 N(7)-H(7N) 0.85(2) N(11)-H(11N) 0.79(2) C(5)-C(1)-C(2) 107.20(14) C(5)-C(1)-C(6) 126.16(14)

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C(2)-C(1)-C(6) 126.62(15) C(5)-C(1)-Fe(1) 69.35(9) C(2)-C(1)-Fe(1) 69.46(9) C(6)-C(1)-Fe(1) 127.70(11) C(3)-C(2)-C(1) 108.39(15) C(3)-C(2)-Fe(1) 69.44(9) C(1)-C(2)-Fe(1) 69.57(9) C(3)-C(2)-H(2) 125.8 C(1)-C(2)-H(2) 125.8 Fe(1)-C(2)-H(2) 126.8 C(2)-C(3)-C(4) 107.96(15) C(2)-C(3)-Fe(1) 69.80(9) C(4)-C(3)-Fe(1) 69.72(9) C(2)-C(3)-H(3) 126.0 C(4)-C(3)-H(3) 126.0 Fe(1)-C(3)-H(3) 126.0 C(5)-C(4)-C(3) 108.05(15) C(5)-C(4)-Fe(1) 69.55(9) C(3)-C(4)-Fe(1) 69.49(10) C(5)-C(4)-H(4) 126.0 C(3)-C(4)-H(4) 126.0 Fe(1)-C(4)-H(4) 126.6 C(4)-C(5)-C(1) 108.39(14) C(4)-C(5)-Fe(1) 69.68(9) C(1)-C(5)-Fe(1) 69.72(9) C(4)-C(5)-H(5) 125.8 C(1)-C(5)-H(5) 125.8 Fe(1)-C(5)-H(5) 126.4 N(7)-C(6)-C(1) 110.46(13) N(7)-C(6)-H(6A) 109.6 C(1)-C(6)-H(6A) 109.6 N(7)-C(6)-H(6B) 109.6 C(1)-C(6)-H(6B) 109.6 H(6A)-C(6)-H(6B) 108.1 N(7)-C(8)-C(9) 113.77(13) N(7)-C(8)-H(8A) 108.8 C(9)-C(8)-H(8A) 108.8 N(7)-C(8)-H(8B) 108.8 C(9)-C(8)-H(8B) 108.8 H(8A)-C(8)-H(8B) 107.7 C(23)-C(9)-C(22) 109.22(14) C(23)-C(9)-C(8) 107.57(14) C(22)-C(9)-C(8) 111.08(13) C(23)-C(9)-C(10) 107.59(13) C(22)-C(9)-C(10) 109.76(14) C(8)-C(9)-C(10) 111.52(13) N(11)-C(10)-C(9) 111.41(13) N(11)-C(10)-H(10A) 109.3 C(9)-C(10)-H(10A) 109.3 N(11)-C(10)-H(10B) 109.3 C(9)-C(10)-H(10B) 109.3 H(10A)-C(10)-H(10B) 108.0 N(11)-C(12)-C(13) 123.67(16) N(11)-C(12)-C(21) 119.83(14) C(13)-C(12)-C(21) 116.50(15) C(12)-C(13)-C(14) 119.31(16) C(12)-C(13)-H(13) 120.3 C(14)-C(13)-H(13) 120.3 N(15)-C(14)-C(13) 126.63(16) N(15)-C(14)-H(14) 116.7 C(13)-C(14)-H(14) 116.7 N(15)-C(16)-C(17) 117.30(15) N(15)-C(16)-C(21) 123.98(16) C(17)-C(16)-C(21) 118.71(15) C(18)-C(17)-C(16) 120.25(15) C(18)-C(17)-H(17) 119.9 C(16)-C(17)-H(17) 119.9 C(17)-C(18)-C(19) 121.98(16) C(17)-C(18)-Cl(1) 119.52(13)

C(19)-C(18)-Cl(1) 118.50(13) C(20)-C(19)-C(18) 118.45(16) C(20)-C(19)-H(19) 120.8 C(18)-C(19)-H(19) 120.8 C(19)-C(20)-C(21) 121.81(15) C(19)-C(20)-H(20) 119.1 C(21)-C(20)-H(20) 119.1 C(20)-C(21)-C(16) 118.71(15) C(20)-C(21)-C(12) 122.97(14) C(16)-C(21)-C(12) 118.29(14) C(9)-C(22)-H(22A) 109.5 C(9)-C(22)-H(22B) 109.5 H(22A)-C(22)-H(22B) 109.5 C(9)-C(22)-H(22C) 109.5 H(22A)-C(22)-H(22C) 109.5 H(22B)-C(22)-H(22C) 109.5 C(9)-C(23)-H(23A) 109.5 C(9)-C(23)-H(23B) 109.5 H(23A)-C(23)-H(23B) 109.5 C(9)-C(23)-H(23C) 109.5 H(23A)-C(23)-H(23C) 109.5 H(23B)-C(23)-H(23C) 109.5 C(28)-C(24)-C(25) 108.11(18) C(28)-C(24)-Fe(1) 69.44(11) C(25)-C(24)-Fe(1) 69.50(10) C(28)-C(24)-H(24) 125.9 C(25)-C(24)-H(24) 125.9 Fe(1)-C(24)-H(24) 126.7 C(24)-C(25)-C(26) 107.88(17) C(24)-C(25)-Fe(1) 69.92(10) C(26)-C(25)-Fe(1) 69.44(10) C(24)-C(25)-H(25) 126.1 C(26)-C(25)-H(25) 126.1 Fe(1)-C(25)-H(25) 126.1 C(25)-C(26)-C(27) 108.05(17) C(25)-C(26)-Fe(1) 69.86(10) C(27)-C(26)-Fe(1) 69.51(10) C(25)-C(26)-H(26) 126.0 C(27)-C(26)-H(26) 126.0 Fe(1)-C(26)-H(26) 126.2 C(28)-C(27)-C(26) 107.85(17) C(28)-C(27)-Fe(1) 69.84(11) C(26)-C(27)-Fe(1) 69.65(10) C(28)-C(27)-H(27) 126.1 C(26)-C(27)-H(27) 126.1 Fe(1)-C(27)-H(27) 126.0 C(24)-C(28)-C(27) 108.11(16) C(24)-C(28)-Fe(1) 70.03(11) C(27)-C(28)-Fe(1) 69.45(10) C(24)-C(28)-H(28) 125.9 C(27)-C(28)-H(28) 125.9 Fe(1)-C(28)-H(28) 126.2 C(34)-C(29)-C(30) 117.98(17) C(34)-C(29)-C(35) 121.04(17) C(30)-C(29)-C(35) 120.98(18) C(31)-C(30)-C(29) 121.26(18) C(31)-C(30)-H(30) 119.4 C(29)-C(30)-H(30) 119.4 C(30)-C(31)-C(32) 120.28(18) C(30)-C(31)-H(31) 119.9 C(32)-C(31)-H(31) 119.9 C(31)-C(32)-C(33) 119.54(18) C(31)-C(32)-H(32) 120.2 C(33)-C(32)-H(32) 120.2 C(32)-C(33)-C(34) 120.13(18) C(32)-C(33)-H(33) 119.9 C(34)-C(33)-H(33) 119.9 C(33)-C(34)-C(29) 120.80(17) C(33)-C(34)-H(34) 119.6

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C(29)-C(34)-H(34) 119.6 C(29)-C(35)-H(35A) 109.5 C(29)-C(35)-H(35B) 109.5 H(35A)-C(35)-H(35B) 109.5 C(29)-C(35)-H(35C) 109.5 H(35A)-C(35)-H(35C) 109.5 H(35B)-C(35)-H(35C) 109.5 C(8)-N(7)-C(6) 111.59(13) C(8)-N(7)-H(7N) 110.3(14) C(6)-N(7)-H(7N) 106.8(14) C(12)-N(11)-C(10) 125.10(14) C(12)-N(11)-H(11N) 120.5(15) C(10)-N(11)-H(11N) 113.2(15) C(14)-N(15)-C(16) 115.20(14) C(27)-Fe(1)-C(26) 40.84(7) C(27)-Fe(1)-C(3) 159.54(8) C(26)-Fe(1)-C(3) 122.82(7) C(27)-Fe(1)-C(5) 107.20(7) C(26)-Fe(1)-C(5) 121.28(7) C(3)-Fe(1)-C(5) 68.71(7) C(27)-Fe(1)-C(4) 123.12(8) C(26)-Fe(1)-C(4) 106.52(7) C(3)-Fe(1)-C(4) 40.80(7) C(5)-Fe(1)-C(4) 40.77(6) C(27)-Fe(1)-C(28) 40.71(8) C(26)-Fe(1)-C(28) 68.48(7) C(3)-Fe(1)-C(28) 158.01(8) C(5)-Fe(1)-C(28) 124.16(8) C(4)-Fe(1)-C(28) 160.22(8) C(27)-Fe(1)-C(2) 158.23(7) C(26)-Fe(1)-C(2) 159.79(7) C(3)-Fe(1)-C(2) 40.76(7) C(5)-Fe(1)-C(2) 68.60(7) C(4)-Fe(1)-C(2) 68.53(7) C(28)-Fe(1)-C(2) 122.73(8) C(27)-Fe(1)-C(25) 68.59(7)

C(26)-Fe(1)-C(25) 40.69(7) C(3)-Fe(1)-C(25) 106.86(7) C(5)-Fe(1)-C(25) 156.88(7) C(4)-Fe(1)-C(25) 121.12(7) C(28)-Fe(1)-C(25) 68.40(8) C(2)-Fe(1)-C(25) 123.76(7) C(27)-Fe(1)-C(1) 121.89(7) C(26)-Fe(1)-C(1) 157.43(7) C(3)-Fe(1)-C(1) 69.01(6) C(5)-Fe(1)-C(1) 40.93(6) C(4)-Fe(1)-C(1) 68.89(6) C(28)-Fe(1)-C(1) 107.96(7) C(2)-Fe(1)-C(1) 40.97(6) C(25)-Fe(1)-C(1) 160.66(7) C(27)-Fe(1)-C(24) 68.37(8) C(26)-Fe(1)-C(24) 68.31(8) C(3)-Fe(1)-C(24) 122.00(8) C(5)-Fe(1)-C(24) 160.95(8) C(4)-Fe(1)-C(24) 157.25(8) C(28)-Fe(1)-C(24) 40.53(9) C(2)-Fe(1)-C(24) 108.24(8) C(25)-Fe(1)-C(24) 40.58(7) C(1)-Fe(1)-C(24) 124.41(7) ___________________________________________ Symmetry transformations used to generate equivalent atoms Hydrogen Bonds for 15. Donor --- H....Acceptor [ ARU ] D - H H...A D...A D - H...A ----------------------------------------------------------------------------------------------- N(11) --H(11N) ..N(7) [ ] 0.79(2) 2.11(2) 2.807(2) 148(2) :

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IV. Biological Activity Studies

MDA-MB-435S

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Compound 14 vs. MDA-MB-435S

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Compound 17 vs. MDA-MB-435S

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Compound 15 vs. MDA-MB-435S

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Compound 18 vs. MDA-MB-435S

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8, 9, 13, 14, 15 tested as hexuplicates. The incubator was run without CO2. Condensation in the 96 well-plates was a recurring problem, leading to varying read-out for equi-concentrated wells. The problem occured mostly on the outmost wells, even though a protective well-barrier with water was placed around the 6 x 10 grid. IC50 derived from a sigmoidal curve fit (variable slope) with top and bottom constrained to 100 % and 0 %, respectively. Bottom constraint was not used for compound 9. Data points are the mean value, error bars are displayed as standard deviation (SD). Software used: GraphPad Prism 4.0.

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Caco-2

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Compound 8 vs. Caco-2

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Compound 9 vs. Caco-2

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Compound 13 vs. Caco-2

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Compound 16 vs. Caco-2

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Compound 14 vs. Caco-2

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Compound 17 vs. Caco2

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Compound 15 vs. Caco2

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Compound 18 vs.Caco2

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IC50 derived from a sigmoidal curve fit (variable slope) with top and bottom constrained to 100 % and 0 %, respectively. Data points are the mean value, error bars are displayed as standard deviation (SD). Software used: GraphPad Prism 4.0.

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MCF-10A

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Chloroquine vs. MCF-10A

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Compound 8 vs. MCF-10A

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Compound 9 vs. MCF-10A

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Compound 13 vs. MCF-10A

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50

75

100

125 EC50 1.506

-0.5 0.0 0.5 1.0 1.5log c (μg/mL)

Surv

ival

(%)

Compound 16 vs. MCF-10A

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25

50

75

100

125 EC50 2.272

-0.5 0.0 0.5 1.0 1.5log c (μg/mL)

Surv

ival

(%)

Electronic Supplementary Material (ESI) for Dalton TransactionsThis journal is © The Royal Society of Chemistry 2012

Page 26: 1,2-Disubstituted Ferrocenyl Carbohydrate Chloroquine ... · S1 Supporting Information 1,2-Disubstituted Ferrocenyl Carbohydrate Chloroquine Conjugates as Potential Antimalarial Agents

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Compound 14 vs. MCF-10A

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50

75

100

125 EC50 0.8991

-0.5 0.0 0.5 1.0 1.5log c (μg/mL)

Surv

ival

(%)

Compound 17 vs. MCF10A

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50

75

100

125

-0.5 0.0 0.5 1.0 1.5

EC50 1.059

log c (μg/mL)

Surv

ival

(%)

Compound 15 vs. MCF-10A

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50

75

100

125 EC50 2.141

-0.5 0.0 0.5 1.0 1.5log c (μg/mL)

Surv

ival

(%)

Compound 18 vs. MCF-10A

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50

75

100

125

-0.5 0.0 0.5 1.0 1.5

EC50 3.689

log c (μg/mL)

Surv

ival

(%)

IC50 derived from a sigmoidal curve fit (variable slope) with top and bottom constrained to 100 % and 0 %, respectively. Data points are the mean value, error bars are displayed as standard deviation (SD). Software used: GraphPad Prism 4.0.

Electronic Supplementary Material (ESI) for Dalton TransactionsThis journal is © The Royal Society of Chemistry 2012